AU672627B2

AU672627B2 - Ureido-acetamide derivatives, preparation thereof and drugs containing same

Info

Publication number: AU672627B2
Application number: AU49655/93A
Authority: AU
Inventors: Marie-Christine Dubroeucq; Claude Guyon
Original assignee: Rhone Poulenc Rorer SA
Current assignee: Aventis Pharma SA
Priority date: 1992-09-11
Filing date: 1993-09-06
Publication date: 1996-10-10
Anticipated expiration: 2013-09-06
Also published as: ES2099973T3; KR950703579A; FR2695643A1; RU95109148A; ZA936603B; HU9500710D0; DE69308865T2; IL106963A0; ATE150030T1; US5663204A; CA2144039A1; EP0662081A1; JPH08503696A; IL106963A; DK0662081T3; FR2695643B1; NZ255450A; GR3022796T3; EP0662081B1; HUT73170A

Abstract

PCT No. PCT/FR93/00847 Sec. 371 Date Mar. 10, 1995 Sec. 102(e) Date Mar. 10, 1995 PCT Filed Sep. 6, 1993 PCT Pub. No. WO94/06825 PCT Pub. Date Mar. 31, 1994This invention relates to compounds of formula (I), in which R denotes a hydrogen atom or a methoxy radical. The invention also concerns the salts of said compounds, their racemic forms, their enantiomers, the preparation of said derivatives and drugs containing same.

Description

A.

-OPI DATE 12/04/94 APPLN. ID 49655/931 f* IIII II~~II lI AOJP DATE 07/07/94 PCT NUMBER PCT/FR93/00847 AU9349655 DEM, CT) (51) Classification Internationale des brevets 5:(11) Numi~ro de publication Internationale: WO 94/06825 C07K 5/06, A61K 37/02 A1 (43) Date de publication Internationale: 31 mars 1994 (31,03.94) (21) Numfro de In demande Internationale: PCT/FR93/00847 (74) Mandataire: MORVAN, Micl:~le; Rh6ne-Poulenc Rorer Direction Brevets, 20, avenue Raymond-Aron, F- (22) Date de d~p~t international: 6 septembre 1993 (06.09.93) 92165 Antony-C~dex (FR).

Donn~es relatives A Ia priorit6: (81) Etats d(~sign~s: AU, CA, HU, JP, KR, NO, NZ, RU, US, 92/10838 11 septembre 1992 (11.09.92) FR brevet curop~en (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).

(71) D36posant (pour tous Ics Etats d~sign~s sauf US): RHONE- POULENC RORER S.A. [FR/FR]; 20, avenue Ray- Publi~e mond-Aron, F-92 160 Antony A'ec rapport de recherche internaionale.

(72) Inventeurs; et

N

Inventeurs/D~posants (US seulement) DUBROEUCQ, Ma- r rie-Christine [FR/FR]; 13, villa de Malleville, F-95880 Enghien-les-Bains GUYON, Claude [FR/FR]; 17'27 his, avenue Henri-Martin, F-94 100 Saint-Maur-des-Foss~s (FR).

(54) Title: UREIDO-ACETAMIDE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME (54)Titre: DERIVES D'UREIDO-ACETAMIDE, LEUR PREPARATION ET LES MEDICAMENTS LES CONTENANT t CH -CO-NjO 1

CH

3 C0-CH 2 -NH-C0-NH

CH

S0 3

H

Irow) (57) Abstract Compounds of formula in which R denotes a hydrogen atom or a methoxy radical. The invention also concerns the salts of said compounds, their racemic forms, their enantiomers, the preparation of said derivatives and drugs containing same.

(57) Ahr~g6 Composes de formule dans laquelle R repr6sente un atome d'hydrog~ne ou un radical m6thoxy, leurs sels, leurs rac~miques, leurs 6nantiom~res, leur preparation et les m~dicaments les contenant.

Ar--.

Ui44 WO 94/06825 1 PCT/FR93/00847 UREIDOACETAMIDE DERIVATIVES. THEIR PREPARATION AND THE MEDICAMENTS CONTAINING THEM In Patent Applications WO 91/12264 and WO 91/13907, ureidoacetamide derivatives are described which are useful as cholecystokinin (CCK) and gastrin antagonists.

It has now been found that the compounds of formula:

CH-CO-N

H C H 3

CO-CH

2 -NH-CO-NH

Q

R

,CH

3 CH j

SO

3

H

in which R represents a hydrogen atom or a methoxy radical, their salts, their racemates and their enantiomers unexpectedly have CCK antagonist properties which are much better than those of the ureidoacetamides of Patent Applications WO 91/12264 and WO 91/13907.

The subject of the present invention is thus the compounds of formula their salts, their enantiomers, their preparation and the medicaments containing them.

The compounds of formula can be prepared by reacting a derivative of formula: 1 Lu^ 1 2 CH2-CO-N -N 3 n

CO-CH

2

-NH-CO-N

R aN in which R represents a hydrogen atom or a methoxy radical, with an amine of formula:

CH

3

H

2 N

SO

3 H (III) in the form of a salt.

This reaction is generally carried out in an inert solvent, such as benzene or toluene, at the boiling temperature of the reaction mixture.

Tetraalkylammonium or trialkylphenylammonium salts, and preferably tetra-n-butylammonium salts, can be used as salts.

The derivatives of formula (II) can be obtained by application or adaptation of the methods described in the Patent Applications WO 91/12264 and WO 91/13907.

SThe enantiomers can be prepared from the chiral precursors of the compound of formula (III).

Preferably, the enantiomers are prepared from a tetraalkylammonium salt (Form B) of the amine of formula (III) or from the hydroquinine salt (Form A) of Sthe amine of formula (III).

4R4 by the usual known methods, for example by crystallisation, precipitation, chromatography or extraction.

The compounds of formula and their enantiomers can be converted to metal salts or to addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by reacting a metal base (alkali metal or alkaline-earth metal, for example), ammonia, an amine or a salt of an organic acid with a compound of formula or its enantiomers, in a solvent.

As examples of pharmaceutically acceptable salts, there can be mentioned the salts with alkali metals (sodium, potassium, lithium) or with alkalineearth metals (calcium, magnesium), the ammonium salt, or the salts of nitrogenous bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-pphenethylamine, choline, arginine, leucine, lysine, Nmethylglucamine).

The compounds of formula and their enantiomers have advantageous pharmacological properties. These compounds have a strong affinity for cholecystokinin (CCK) and gastrin receptors and are thus useful in the treatment and prevention of disorders linked to CCK and to gastrin in the nervous system and the gastrointestinal system.

In this way, these compounds can be used for

K-.

e can4be conver oeaslsr adi t h n b a

I

V

i

I'I

1 r~i:Cr~*C~iiCGJla~k.

'ba,

B

i i the treatment of the prevention of psychoses, of anxious disorders, of panic attacks, of Parkinson's disease, of tardive dyskinesia, of irritable bowel syndrome, of acute pancreatitis, of ulcers, of disorders of intestinal motility, of certain tumours sensitive to CCK, as an appetite regulator, in weaning from chronic treatments and alcohol or medicinal abuse, and as a pupil constrictor.

These compounds also have a potentiating effect on the analgesic activity of narcotic and nonnarcotic medicaments. Additionally, they can have their own analgesic effect.

Moreover, the compounds having a high affinity for CCK receptors modify memorising abilities.

Consequently, these compounds can be effective in memory disorders.

Affinity of the compounds of formula for CCK receptors was determined according to a technique inspired by that of A. Saito et al. Neuro. Chem., 37, 483-490 (1981) in the cerebral cortex.

In this test, the ICs 5 of the compounds of formula is less than 2 nM.

Moreover, it is known that the products which recognise the central receptors of CCK have a similar specificity for the receptors of gastrin in the gastrointestinal tract (Bock et al., J. Med. Chem., 32, 16-23 (1989); Reyfeld et al., Am. J. Physiol., 240, G 255-266 (1981); Beinfeld et al., Neuropeptides, 3, OT 2A r 1_ -r 411-427 (1983)).

The compounds of formula have a low toxicity. Their subcutaneous LDso in mice is greater than 40 mg/kg.

The following compounds are particularly advantageous: (RS)-1-(3-{3-[N-(3-Methoxyphenyl)-N-(N-methyl- N-phenylcarbamoylmethyl)carbamoylmethyllureido}phenyl}ethanesulphonic acid (-)-1-{3-3-[N-(3-Methoxyphenyl)-N-(N-methyl- N-phenylcarbamoylmethyl)carbamoylmethyl] ureido)phenyl}ethanesulphonic acid (RS)-1-(3-(3-[N-(Methyl-N-phenylcarbamoylmethyl)- N-phenylcarbamoylmethyl]ureido}phenyl}ethanesulphonic acid.

The following examples illustrate the invention without limiting it.

EXAMPLE 1 6.7 g of tetra-n-butylammonium (RS)-1- (3-aminophenyl)ethanesulphonate are added to a solution of 5.5 g of 2-{2-E(1-imidazolyl)carboxamido-N-(3-methoxyphenyl)acetamido}-N-methyl-N-phenylacetamide in 120 cm 3 of toluene. The reaction mixture is stirred at reflux for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 45 0 C. The residue is dissolved in 200 cm 3 of methylene chloride and the solution obtained is washed with 200 cm' of a 2N aqueous hydrochloric acid solution and then with 2 times 200 cm'

II

T*

-Q

I 4- 4

A

1i of water. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. The crude product obtained is stirred for 30 minutes in 100 cm 3 of diisopropyl ether. The insoluble product is separated by filtration and then dissolved in 20 cm 3 of acetone. 3.0 g of potassium nonafluorobutanesulphonate in solution in cm 3 of acetone are added and then 25 cm 3 of diisopropyl ether are added. The insoluble product is separated by filtration, washed with 2 times 5 cm 3 of acetone and then 4 times 15 cm 3 of diisopropyl ether and air-dried.

There are thus obtained 5.5 g of potassium {3-[N-(3-methoxyphenyl)-N-(N-methyl-Nphenylcarbamoylmethyl)carbamoylmethyl]ureido}phenyl}ethanesulphonate melting at approximately 180 0

C.

N.M.R. spectrum: (300 MHz; d6-DMSO): 6(ppm): 1.43 J 7 Hz, 3H, -CH(CH 3 3.18 [broad s, 3H, -N(CH 3 3.60 [mt, 1H, -CH(CH 3 3.65 [broad d, J 5 Hz, 2H, -CO(CH 2

)NH-]

3.79 3H, -OCH 3 4.09 [large, 2H, -CO(CH,)N<] 6.28 [broad t, J 5 Hz, 1H, -NH-] 6.86 J 7.5 Hz, 1H, -CH of the N-(3-methoxyphenyl)] [mt, 4H, aromatic protons] from 6.95 to 7.15 IL I. 'toI I I I I 7 7.17 [broad s, 1H, -C 6

H

4 of the N-(3-methoxyphenyl) from 7.30 to 7.50 [mt, 11H, aromatic protons] 8.80 [broad s, 1H, -CO-NH-Ar].

Tetra-n-butylammonium (RS)-1-(3-aminophenyl)ethanesulphonate can be prepared in the following way: 0.8 g of 5 palladium charcoal is added to a solution of 17.8 g of tetra-n-butylammonium nitrophenyl)ethanesulphonate in 200 cm 3 of ethanol. The suspension is stirred for 3 hours at a temperature in the region of 25 0 C under a hydrogen atmosphere (100 kPa). The catalyst is separated by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. There are thus obtained 16.7 g of tetra-n-butylammonium (RS)-1-(3-aminophenyl)ethanesulphonate in the form of an oil used as is in subsequent syntheses.

Tetra-n-butylammonium (RS)-1-(3-nitrophenyl)ethanesulphonate can be prepared in the following way: 25.3 g of (RS)-l-(l-bromoethyl)-3.-nitrobenzene are added to a solution of 20.8 g of sodium sulphite in 260 cm 3 of water. The reaction mixture is stirred at 80 0

C

for 5 hours, cooled to approximately 25°C and run into litres of a 0.5M aqueous potassium dihydrogenphosphate solution. 40 g of tetra-nbutylammonium hydrogensulphate are added. The mixture is extracted with 3 times 500 cm 3 of methylene chloride.

LU

ui i

I

I t 8 The combined organic phases are washed with 2 times 500 cm 3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. There are thus obtained 51.4 g of tetra-n-butylammonium (RS)-1-(3-nitrophenyl)ethanesulphonate in the form of an oil used as is in subsequent syntheses.

(RS)-1-(1-Bromoethyl)-3-nitrobenzene can be prepared according to the method described by E. Felder et al., J. Med. Chem., 13, 559 (1970).

(-Imidazolyl)carboxamido]-N-(3methoxyphenyl)acetamido}-N-methyl-N-phenylacetamide can be prepared in the following way: a solution of 3.1 g of 2-[2-amino-N-(3-methoxyphenyl)acetamido]-N-methyl-Nphenylacetamide in 30 cm 3 of anhydrous tetrahydrofuran is added to a solution of 3.0 g of N,N'-carbonyldiimidazole in 30 cm 3 of anhydrous tetrahydrofuran. The solution is stirred for 16 hours at a temperature in the region of 25 0 C and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. The residue is dissolved in 50 cm 3 of ethyl acetate and the solution obtained is washed with 4 times 30 cm 3 of water. The organic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa) at 4°C. There are obtained, after recrystallisation from ethyl acetate, 3.5 g of 2-{2- [(1-imidazolyl)carboxamido]-N-(3-methoxyphenyl)acetamido}-N-methyl-N-phenylacetamide melting at 146 0

C.

.0 4/7 00 9 2-[2-Amino-N-(3-methoxyphenyl)acetamido]- N-methyl-N-phenylacetamide can be prepared in the following way: 1.3 g of hydrazine hydrate are added to a solution of 5.5 g of 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido]-N-methyl-N-phenylacetamide in 60 cm 3 of methanol. The reaction mixture is stirred at reflux for minutes and then, after cooling, 100 cm 3 of water are added. The mixture is concentrated to approximately 100 cm 3 then brought to a pH of 9 with a 2N aqueous sodium hydroxide solution and extracted with 2 times cm 3 of ethyl acetate. The combined organic phases are washed with 2 times 50 cm 3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. There are thus obtained 3.0 g of 2-[2-amino-N-(3-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide in the form of an oil used as is in subsequent syntheses.

2- N-(3-Methoxyphenyl)-2-phthalimidoacetamidol-N-methyl-N-phenylacetamide can be prepared in the following way: 10 cm 3 of dimethylformamide and then, over 1 hour, 30.2 g of oxalyl dichloride are added to a J suspension of 80.6 g of 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido]acetic acid in 900 cm 3 of 1,2-dichloroj ethane. The mixture is stirred for 2 hours at a temperature in the region of 25°C and then 58.6 g of N-methylaniline are added over 45 minutes. The reaction mixture is stirred for 2 hours at a temperature in the s/,A region of 25°C, washed with 2 times 500 cm 3 of water and //1jj J 1s then 300 cm 3 of a saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. The residue is stirred for 1 hour in 300 cm 3 of diisopropyl ether, the insoluble product is separated by filtration, washed with 3 times 60 cm 3 of diisopropyl ether .id air-dried. There are thus obtained 84 g of 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido]-N-methyl-N-phenylacetamide melting at 137 0

C.

2-[N-(3-Methoxyphenyl)-2-phthalimidoacetamido]acetic acid can be prepared in the following way: 74.0 g of trifluoroacetic acid are added to a solution of 42.0 g of tert-butyl 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido]acetate in 500 cm 3 of methylene chloride. The solution obtained is stirred at reflux for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. The residue is stirred for 1 hour in 100 cm 3 of diisopropyl ether, the insoluble product is separated by filtration, washed with 3 times 40 cm 3 of diisopropyl ether and airdried. There are thus obtained 36 g of 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido]acetic acid melting at 203 0

C.

tert-Butyl 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido] acetate can be prepared in the following way: 14.9 g of an oily suspension (60 by weight) of ITR sodium hydride are added over 30 minutes to a solution Lo 11 of 96 g of N-(3-methoxyphenyl)-2-phthalimidoacetamide in 1000 cm 3 of anhydrous tetrahydrofuran. The suspension is stirred for 4 hours at a temperature in the region of 200C and then 72.7 g of tert-bucyi bromoacetate are added over 15 minutes. The reaction mixture is stirred for 16 hours at a temperature in the region of 250C, slowly hydrolysed with 50 cm 3 of water and then concentrated to dryness under reduced pressure. The residue obtained is stirred for 1 hour in 400 cm 3 of water, the insoluble product is separated by filtration, washed with 3 times 100 cm 3 of water, 2 times 100 cm 3 of diisopropyl ether and air-dried. There are thus obtained 82.0 g of tert-butyl methoxyphenyl)-2-phthalimidoacetamido]acetate melting at 148 0

C.

N-(3-Methoxyphenyl)-2-phthalimidoacetamide can be prepared in the following way: 22.0 g of triethylamine and then 48.0 g of 2-phthalimidoacetyl chloride in solution in 300 cm 3 of methylene chloride are added to a solution of 26.0 g of 3-methoxyaniline in 200 cm 3 of methylene chloride while maintaining the temperature at approximately 20 0 C. The reaction mixture is stirred for 4 hours at this temperature and then 800 cm 3 of water are added. The insoluble product is separated by filtration, washed with 3 times 100 cm 3 of water and air-dried. There are thus obtained 65.0 g of N-(3-methoxyphenyl)-2-phthalimidoacetamide melting at 171 0

C.

9 i L I 0 1 L i-r i 12 2-Phthalimidoacetyl chloride can be prepared according to the method described by W. Grassmann and E. Schulte-Uebbing, Chem. Ber., 83, 244-247, (1950).

EXAMPLE 2 2.7 g of tetra-n-butylammonium 1-(3aminophenyl)ethanesulphonate, form B, are added to a solution of 2.1 g of 2-{2-[(1-imidazolyl)carboxamido]- N-(3-methoxyphenyl)acetamido}-N-methyl-Nphenylacetamide in 130 cm 3 of toluene. The reaction mixture is stirred at reflux for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 45 0 C. The residue is dissolved in 100 cm 3 of methylene chloride and the solution obtained is washed with 50 cm 3 of a 2N aqueous hydrochloric acid solution and then with 2 times 50 cm 3 of water. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. The crude product obtained is stirred for minutes in 50 cm 3 of diisopropyl ether. The insoluble product is separated by filtration and then dissolved in 6 cm 3 of acetone. 1.2 g of potassium nonafluorobutanesulphonate in solution in 3 cm 3 of acetone are added and then 5 cm 3 of diisopropyl ether are added. The insoluble gum is separated and then stirred for 1 hour in 12 cm 3 of an acetone and diisopropyl ether mixture (50/50 by volume). The insoluble product is separated by filtration, washed I with 2 times 5 cm 3 of an acetone and diisopropyl ether IV RA' k T^ _y mixture (50/50 by volume) and then with 4 times 5 cm 3 of diisopropyl ether, and air-dried. There are thus obtained 1.55 g of potassium methoxyphenyl) (N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl) ureido)phenyl)ethanesulphonate melting at approximately 180 0

C.

[a]0 5.00 0.5 (c 0.888 methanol) N.M.R. spectrum: (300 MHz; d6-DMSO: (-)-form) d(ppm): 1.43 J 7 Hz, 3H, -CH(CH3)-] 3.18 [broad s, 3H, -N(CH 3 3.60 [mt, 1H, -CH(CH 3 3.65 [broad d, J 5 Hz, 2H, -CO(CH 2

)NH-]

3.79 3H, -OCH 3 4.09 [large, 2H, -CO(CH 2

)N<

6.28 [broad t, J 5 Hz, 1H, -NH-] 6.86 J 7.5 Hz, 1H, -CH 4 of from 7.17 from 8.80 6.95 to 7.15 7.30 to 7.50 the N-(3-methoxyphenyl)] [mt, 4H, aromatic protons] [broad s, IH, -C 6

H

4 of the N-(3-methoxyphenyl)] [mt, 11H, aromatic protons] [broad s, IH, -CO-NH-Ar].

tetra-n-Butylammonium 1-(3-aminophenyl)ethanesulphonate, form B, can be prepared in the following way: 0.2 g of 5 palladium charcoal is added to a solution of 2.8 g of tetra-n-butylammonium Iu I- 14 1-(3-nitrophenyl)ethanesulphonate, form B, in 50 cm 3 of ethanol. The suspension is stirred for 2 hours at a temperature in the region of 25 0 C under a hydrogen atmosphere (100 kPa). The catalyst is separated by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. There are thus obtained 2.8 g of tetra-n-butylammonium 1-(3-aminophenyl)ethanesulphonate, form B, in the form of an oil used as is in subsequent syntheses.

tetra-n-Butylammonium 1-(3-nitrophenyl)ethanesulphonate, form B, can be prepared in the following way: 5.2 g of potassium nonafluorobutanesulphonate in solution in 12 cm 3 of acetone are added to a solution of 10.5 g of N-benzylquininium 1-(3-nitrophenyl)ethanesulphonate, a mixture of forms A and B (approximately 15/85 in moles), in 16 cm 3 of acetone. The insoluble product is separated by filtration and then dissolved in 9 -cm 3 of watei'. 8.4 cm 3 of a IN aqueous hydrochloric acid solution and 1.15 g of R-(-)-phenylglycinol are added.

The solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) at 50 0 C. The residue obtained is extracted with 3 times 15 cm 3 of acetonitrile at reflux. The organic phases are combined and concentrated to approximately 7 cm 3 after cooling, the crystals are separated by filtration and dissolved w..i in 7.5 cm 3 of a IN aqueous sodium hydroxide solution.

l The solution obtained is washed with 8 times 25 cm 3 of I I~Lp i..i j i I diethyl ether and then 60 cm 3 of a 0.5M aqueous potassium dihydrogenphosphate solution and 2.3 g of tetra-n-butylammonium hydrogensulphate are added. The mixture is extracted with 3 times 30 cm 3 of methylene chloride. The combined organic phases are dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. There are thus obtained 2.8 g of tetra-n-butylammonium l-(3-nitrophenyl)ethanesulphonate, form B, in the form of an oil used as is in subsequent syntheses.

N-Benzylquininium 1-(3-nitrophenyl)ethanesulphonate, a mixture of forms A and B, can be prepared in the following way: 87 g of potassium dihydrogenphosphate and 32.4 g of N-benzylquininium chloride are added to a solution of 17.2 g of potassium (RS)-1-(3-nitrophenyl)ethanesulphonate in 400 cm 3 of water. The mixture is extracted with 2 times 300 cm 3 of methylene chloride. The combined organic phases -are washed with 2 times 200 cm 3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. The foam obtained is dissolved in 120 cm 3 of 2-propanol at reflux. After Icooling, the crystals are separated by filtration and washed with 2 times 15 cm 3 of 2-propanol. There are obtained, after 2 recrystallisations from 350 and 500 cm 3 of 2-propanol, 15.6 g of N-benzylquininium 1-(3nitrophenyl)ethanesulphonate, form A, melting at .approximately 110 0 C. [1]0 151.3° K yo 16 (c 1.009 Methanol). The propanol solutions are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 45°C. There are thus obtained 25.0 g of N-benzylquininium 1-(3-nitrophenyl)ethanesulphonate, a mixture of forms A and B (approximately 15/85 in moles).

Potassium (RS)-1-(3-nitrophenyl)ethanesulphonate can be prepared in the following way: 25.3 g of (RS)-1-(l-bromoethyl)-3-nitrobenzene are added to a solution of 20.8 g of sodium sulphite in 260 cm 3 of water. The reaction mixture is stirred at 80 0 C for hours, cooled to approximately 25 0 C and run into litres of a 0.5M aqueous potassium dihydrogenphosphate solution. 40 g of tetra-nbutylammonium hydrogensulphate are added. The mixture is extracted with 3 times 500 cm 3 of methylene chloride.

The organic phases are washed with 2 times 500 cm 3 of water, dried over magnesium sulphate, and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0

C.

The oil obtained is dissolved in 65 cm 3 of acetone and 34 g of potassium nonafluorobutanesulphonate in solution in 75 cm 3 of acetone are added. The insoluble 7 product is separated by filtration, washed with 3 times cm 3 of diisopropyl ether and air-dried. There are thus obtained 22.4 g of potassium nitrophenyl)ethanesulphonate, melting at a temperature greater than 260 0 C and used as is in subsequent syntheses.

,V 0 z ?/Lii 4Q 'U ~i 17 (RS)-1-(l-Bromoethyl)-3-nitrobenzene can be prepared according to the method described by E. Felder et al., J. Med. Chem., 13, 559 (1970).

EXAMPLE 3 6.7 g of tetra-n-butylammonium aminophenyl)ethanesulphonate are added to a solution of 2.8 g of 2-{2-(1-imidazolyl)carboxamido]-N-phenylacetamido]-N-methyl-N-phenylacetamide in 70 cm 3 of toluene. The reaction mixture is stirred at reflux for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 45 0 C. The residue is dissolved in 100 cm 3 of methylene chloride and the solution obtained is washed with 100 cm 3 of a 2N aqueous hydrochloric acid solution and then with 2 times 100 cm 3 of water. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. The crude product obtained is stirred for 30 minutes in 60 cm 3 of diisopropyl ether.

The insoluble product is separated by filtration and then dissolved in 20 cm 3 of acetone. 1.9 g of potassium nonafluorobutanesulphonate in solution in 10 cm 3 of acetone are added. The insoluble product is separated by filtration, washed with 4 times 5 cm 3 of acetone and then 4 times 8 cm 3 of diisopropyl ether and air-dried.

There are thus obtained 5.5 g of potassium [3-(N-(N-methyl-N-phenylcarbamoylmethyl)-N-phenylcarbamoylmethyl]ureido}phenyl}ethanesulphonate melting at approximately 210 0

C.

18 2-{2-[(1-Imidazolyl)carboxamido}-N-phenylacetamido}-N-methyl-N-phenylacetamide can be prepared in the following way: a solution of 37 g of 2-(2-amino- N-phenylacetamido)-N-methylacetamide in 150 cm 3 of anhydrous tetrahydrofuran is added to a solution of 31 g of N,N'-carbonyldiimidazole in 300 cm 3 of anhydrous tetrahydrofuran. The solution is stirred for 3 hours at a temperature in the region of 25 0 C and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. The residue is dissolved in 500 cm 3 of ethyl acetate and the solution obtained is washed successively with 4 times 300 cm 3 of distilled water and with 300 cm 3 of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. There are obtained, after recrystallisation from ethyl acetate, 33.3 g of 2-{2- [(1-imidazolyl)carboxamido}-N-phenylacetamido}-Nmethyl-N-phenylacetamide melting at 120 0

C.

2-(2-Amino-N-phenylacetamido)-N-methyl-Nphenylacetamide can be prepared in the following way: 0.25 g of hydrazine hydrate is added to a solution of 1.4 g of N-methyl-N-phenyl-2-(N-phenyl-2-phthalimidoacetamido)acetamide in 15 cm 3 of methanol. The reaction mixture is stirred at reflux for 2 hours. After cooling and addition of 5 cm 3 of a 4N aqueous hydrochloric acid solution, the insoluble product is separated by filtration. The filtrate is concentrated to dryness 4UI i 19 under reduced pressure (2.7 kPa)) 30°C. The residue obtained is dissolved in 10 cm 3 of distilled water and then the solution obtained is washed with 10 cm 3 of diethyl ether, basified with 0.5 g of sodium hydroxide pellets and extracted with 2 times 20 cm 3 of ethyl acetate. The combined organic phases are dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 0 C. There is thus obtained 0.9 g of 2-(2-amino-N-phenylacetamido)-Nmethyl-N-phenylacetamide in the form of an oil used as is in subsequent syntheses.

N-Methyl-N-phenyl-2-(N-phenyl-2-phthalimidoacetamido)acetamide can be prepared in the following way: 3.9 g of oxalyl dichloride and then one drop of dimethylformamide are added to a suspension of 10.1 g of 2-(N-phenyl-2-phthalimidoacetamido)acetic acid in 125 cm 3 of 1,2-dichloroethane. The mixture is stirred for 2 hours at a temperature in the region of 25°C and then 7.7 g of N-methylaniline in solution in 30 cm 3 of 1,2-dichloroethane are added. The solution obtained is stirred for 2 hours at a temperature in the region of 0 C and then washed with 2 times 80 cm 3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0

C.

There are obtained, after recrystallisation from diisopropyl ether, 9.6 g of N-methyl-N-phenyl-2-(Nphenyl-2-phthalimidoacetamido)acetamide melting at 4, 216 0

C.

2-(N-Phenyl-2-phthalimidoacetamido)acetic acid can be prepared in the following way: 17.9 g of trifluoroacetic acid are added to a solution of 8 g of tert-butyl 2-(N-phenyl-2-phthalimidoacetamido)acetate in 30 cm 3 of dichloromethane. The solution obtained is stirred at reflux for 1 hour and then concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. There are obtained, after recrystallisation from diisopropyl ether, 5.9 g of 2-(N-phenyl-2-phthalimidoacetamido)acetic acid melting at 224 0

C.

tert-Butyl 2-(N-phenyl-2-phthalimidoacetamido)acetate can be prepared in the following way: 92.4 g of sodium hydrogen carbonate are added to a solution of 207 g of tert-butyl N-phenylglycinate in 500 cm 3 of 1,2-dichloroethane. The suspension is stirred at a temperature in the region of 50C and a solution of 223 g of 2-phthalimidoacetyl chloride in 1100 cm 3 of 1,2-dichloroethane is added. The reaction mixture is stirred at reflux for 4 hours. After separation of the insoluble product by filtration, the filtrate is washed with 300 cm 3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. There are obtained, after recrystallisation from acetonitrile, 236 g of tertbutyl 2-(N-phenyl-2-phthalimidoacetamido)acetate melting at 128 0

C.

tert-Butyl N-phenylglycinate can be prepared in the following way: 58 g of tert-butyl bromoacetate 2 Z.i) 1 i x j) I 21 are added to a solution of 56 g of aniline in 600 cm 3 of 1,2-dichloroethane and the solution obtained is stirred at reflux for 48 hours. After cooling, the insoluble product is separated by filtration and the filtrate is washed with 200 cm 3 of a 0.1N aqueous hydrochloric acid solution and with 3 times 200 cm 3 of distilled water.

The organic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. There are thus obtained 54 g of tert-butyl N-phenylglycinate in the form of an oil used as is in subsequent syntheses.

2-Phthalimidoacetyl chloride can be prepared according to the method described by W. Grassman and E. Schulte-Uebling, Chem. Ber., 83, 244 (1950).

The medicaments according to the invention consist of a compound of formula in the free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which can be inert or physiologically active. The medicaments according to the invention can be used -orally, parenterally, rectally or topically.

Tablets, pills, powders (gelatin capsules or cachets), or granules can be used as solid compositions for oral administration. In these compositions, the active principle according to the invention is mixed with one or a number of inert diluents, such as starch, a pt 22 cellulose, sucrose, lactose or silica, under an argon stream. These compositions can also comprise substances other than the diluents, for example one or a number of lubricating agents such as magnesium stearate or talc, a colouring agent, a coating agent (dragbes) or a varnish.

Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil can be used as liquid compositions for oral administration. These compositions can comprise substances other than the diluents, for example wetting, sweetening, thickening, flavouring or stabilising substances.

The sterile compositions for parenteral administration can preferably be aqueous solutions or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic 20 esters, for example ethyl oleate, or other suitable organic solvents can be used as solvent or vehicle.

These compositions can also contain adjuvants, in particular wetting, isotonising, emulsifying, dispersing and stabilising agents. Sterilisation can be carried out in several ways, for example by aseptic filtration, by incorporating sterilising agents in the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid 23 compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, besides the active product, excipients such as cocoa butter, semi-synthetic glycerides or poly(ethylene 1 glycol)s.

The compositions for topical administration

I

can be, for example, creams, lotions, eye drops, mouthwashes, nose drops or aerosols.

In human therapeutics, the compounds according to the invention are particularly useful in the treatment and prevention of disorders linked to CCK I and to gastrin in the nervous system and the gastrointestinal system. These compounds can thus be used in the treatment and prevention of psychoses, i anxious disorders, of panic attacks, of Parkinson's disease, of tardive dyskinesia, of irritable bowel syndrome, of acute pancreatitis, of ulcers, of disorders of intestinal motility, of certain tumours sensitive to CCK, of memory disorders, as analgesics, as potentiation tgents of the analgesic activity of narcotic and non-narcotic analgesic medicaments and as an appetite regulator, in weaning from chronic treatments and alcohol or medicinal abuse and as a constrictor of the pupil of the iris of the eye.

The doses depend on the desired effect, on i Irr oj l7i 24 the duration of treatment and on the administration route used; they are generally between 0.05 g and 1 g per day orally for an adult with unit doses ranging from 10 mg to 500 mg of active substance.

Generally, the doctor will determine the appropriate dosage depending on the age, weight and all the other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention: EXAMPLE A Gelatin capsules containing 50 mg of active product are prepared, according to the usual technique, which have the following composition: Potassium (RS)-1-{3-{3-[N-(3-methoxyphenyl) -N-(N-methyl-N-phenylcarbamoylmethyl)carbamoylmethyl]ureido}phenyl}ethane ulphonate 50 mg Cellulose 18 mg Lactose 55 mg Colloidal silica 1 mg Sodium carboxymethylstarch 10 mg Talc 10 mg Magnesium stearate 1 mg EXAMPLE B Tablets containing 50 mg of active product are prepared, according to the usual technique, which have the following composition: I

A

Potassium (-)-1-{3-{3-[(N-(3-ethoxyphenyl).

N- (N-methyl -N-phenylcarbamoyl methiyl) carbamoylmethyl] ureido~phenyl} 104 mg 40 mg 10 mg Sodium carboxymethylstarch............... 22 mg 10 mg 2mg Colloidal 2 mg Mixture of hydroxymethylcellulose, glycerol and titanium oxide (72/3.5/24.5) q.s. for one coated tablet completed to 245 mg EXAMPL)@ C An injectable solution containing 10 mg of active product is prepared which has the following composition: Potassium (N-methyl-Nphenylcarbaxnoylmethyl) -N-phenylcarbanoyl methyljureido~phenyl~ethanesulphonate 10 mg Benzoic 80 mg Benzyl 0.06 cm 3 Sodium 80 mg 95 0.4 cm 3 Sodium 24 mg Propylene 1.6 cm 3 q.s. for 4 cm 3

Claims

1. Compounds of formula: CH 2 -CO-Nj(I Ip CO-CH- 2 -NH--CO-NH- CJ R /CH 3 CH SO 3 H in which R represents a hydrogen atom or a methoxy radical, their salts, their racemates and their enantiomers.

2. The following compounds: (RS) EN- (3-Methoxyphenyl) (N-methyl- N-phenylcarbamnoylmethyl) carbamoy-lmethyl) ureido) phenyl) ethanesulphonic acid -l-{3-{3-[N-(3-Methoxyphenyl)-N-(N-methyl- N-phenylcarbamoylmethyl) carbamoylmethyll ureido} phenyl~ethanesulphonic acid (RS) EN- (N-Methyl-N-phenylcarbamoyl- methyl) -N-phenylcarbamoylmethyljureido~phenyl)- ethanesulphonic acid and their salts./

3. Process for preparing the compounds of formula characterised in that a derivative of formula: I 27 CH 2 -CO-N O CH 3 (II) CO-CH2NH- CO-N(I R K N in which R represents a hydrogen atom or a methoxy radical, is reacted with an amine of formula: CH 3 H 2 N l SO 3 H (III) in the form of a salt and optionally in the form of an enantiomer, the product is isolated and is optionally converted to a salt and/or the enantiomers are separated.

4. Medicaments comprising, as active principle, at least one compound of formula (I) according to claim 1.

5. Medicaments according to claim 4 which are inhibitors of CCK and of gastrin. .4 ITERNATIONAL SEARCH REPORT 1nin ad AMplcation No IPCT/FR 93/00847 A. LASFICATION OF SUDJECT MAtTER IPC S5 C07K5/O6 A61K37/02 -Acondng to Werrualional Patnt Caiefircon (WPC or to both national clasification and IPC B. FIELDS SEARCHED Mdinimnum doostrunilwz narded (dassiicalon system followed by clasification symbols) IPC 5 C07K Documentation Mearched other shan minimumn documentation to the exent that such documents are included in thec fields searched Elcrncdata base conuited durig the inaatoal Mearch (name or data but and., where practical, search lerns used) X WO,A,91 12264 (RHONE-POULENC RORER 22 August 1991 cited in the application see claims 1,6,16-18; examples 102,117 j] Pirier doeumntns am Hond in the cutnuanoan of box C. Patent family memnbers arc listed in anx *Special categoeses of cited documents: Ilw document published after the international filing date dewnnt efinng he e~aistae ofthe~ ~oroity date and not in conflict with the appllca"on but W docmentdefiing te scecr stae of he at whth i ot ti understnd thet jmnciple or theory undchling she coaided to be of paricular reevweenenio WE eaurler document butt publihdon orateh inentinl 'X document of particular relevanc;telimdnvbn Miing dule eannot be eonsidered novel or cannot b en: eed *L document which may ftow doubts an piority dlaim(s) or involve an invetive step when the document is taken alone which is cited to eatablMs thte publication data of another document of pauticular relevance; the claimed invention -ciaitn or other special son (us specified) cannot be condered to involve an inventive step when the lo, doctnet refuting so an oral iscdosure, use, exhaibition or document iscombined with one or more other such dow.- other means inenus. mach cominsiatiac bang obvious to a peruon duilled -I documn P*Ipbted peior to she intemsdonal Miig dale bultth ar tan the peicety delm claimed 'W document nmber of the same parent family Dat of she actual completion atU thentional Mearch Dali of ma"ing of the itnational search repast 9 December 1993 2 2 -12- 1993 Name and mailing address of the ISA Authorized officer EuapaPatenttOffie, P.B. 312 l'sMuan 2 NL 2210 EV Rliwik Tel. (-+3170)340-2B40 T31651poi Fuhr al Fwc 31-70) 340-3016 ur C Form. PCTSA'at (suemi skes (muy WM~J I INTERNATIONAL SEo4JICH REPORT .maiAppouaoONo Infomadoonpantfai~ymbaiPCT/FR 93/00847 Paient documen Pblication IPlant family Publication cited in search report dae 1 mcmber(s) daue WO-A-9 112264 22-08-91 FR-A- FR-A- FR-A- AU-B- AU-A- EP-A- 2658196 2667319 2667863 639081 7329591 0514442

16-08-91 03-04-92

17-04-92 15-07-93 03-09-91

25-11-92 I PCTjISA/210 frutmt &uMY M miami (IM9) ,~ip I .1 0 c 0 RAPPORT DE RECHERCHE INTERNATIONALE Dar Inswnaal No PCT/FR 93/00847 A.C ASMN DE LOBJEr DE LA DEMANDE CB5 C07K5/06 A61037/02 Seton1 I& Cl~iAmllin, intWAouuonaiC des brevets (CIB) ci la fais seon I& clasiflcathon nationale etla CIB B. DOMAINES SUR. LESQUELS LA RECHERCHE A PORTE Docaentasbm youumaie cou ic (sjctimn de clssifcaaiomuvi dos "hioes de cuucnt) CIB 5 C07K .1 Documnsiaon conxultbe autre "u Ia. documentahon minmahc dans I& memii aft as documnts reiewnt des dotone, air lesqueis a portt Is, recherche Butc dc doone tectmeqale coasultie au emui de I& rechercbe tmiaaonuhe (nom deis base de dcozsns, at si omla est riaihable, tames de recherdc utiisix) C. DOCUMENTS CONSIDERES COMME PERTINENTS Cattgodec Idcadfhcation dea documas dit~, ahe It cas tchiant, llm~ndac des p-9ci pertines no. des re1'n~cancn"s i x WO,A,91 12264 (RHONE-POULENC RORER 1,3-5 22 AoUt 1991 citd dans la demlande. voir revendications 1,6,16-18; exemples 102,117 LIVoir is site du cadre C pow Ia fin de Islis des document j, Les document: de familks de btevete sont izadiquis to ansicic Cahgmis sedaus d dOCn~eU iihI document ulhicit publit apts Ia date de pt int ntioflsl o a *A dcumet d~lnaunt ~tatgbiaai e a e~qu,__data e i fofl& t hnappartecaat pas A I'Ctat dc la ehiu douet eiisatIat une d atchiuno nrt.= masaepur T~pedeI snp couidtr cmm G iuiftmu PpDriWti 0~l 1&i 1a tidrecntiath c I o'vzin documuent anthir.r mats -uli i la d"to de depat Ineain otn~ 'natc eadq~ pu CiiipretioU i crt comme nmiveli Cu comme i lqut tine sb IV doeunnent pocsvat cr sin dwoestiar ussi revcad~on de intie par raua document consdir& io tt prioriti ou dcit pour dtuirish da de pobticatim (runt 'Y documnt pstilitrement psstni; l'inventin iccdiquse autr citation ou pow mec ralson qpiile (seile qmiu~e) sic past W u~ elm c come impfiqmst mie activith insventsi documnt it rfasat A umi ivuhgation ortah, Aium usage. A hnueIdomesct assoct A um ci piusicn surc uc espoato ass tau su mies ocaine imtn na uemi comniniio ut tvidesni documnt pssbhi* avant Is date di dOpt internl 0011, mans pow ine per500fli duimtc posisuten~t A la date dc poorsewsdqtc document qii et parsh deI&i mmin lamilic de brevets Date A haquedi I& medscds inltflnsAtoi a Ai u9 ffctivcamt aeevte Dame d'expidtion dui present raport de rechserche intcmnatiocsul 9 Odcembre 1993 2 2 -12- 1993 Nom et adsiae poetic de l'aha-iimtiu dcaro de I& ueduedc iasanSaiceade Fasiouloenfre aU9milh Offie Europica, des Draetsi, P.B. WsiA Pa~lsntl 2 NL -2290 HV Riiswuk Tel. (+317t)3402X4% Tzh31 651 a"pid,Fur C Fa= 31-70) 340-3016 ur C P KuhiuPTISA/210 (immikSS fteW) (14108et IM)~ 4. 6 RAPPORT DE RECHERCHE INTERNATIOI4ALE Rculdgemaou reaafg n LU? neMtx de famillel de kewU Den AnumadUMINo PET/FR 93/00847 r Documemnt brent citb P awe de IMembre(s) de la Date de au rmpport de recherchie Aulcation famille de brevets) publicasion WO-A-9112264 22-08-91 FR-A- FR-A- FR-A- AU-B- AU-A- EP-A- 2658196 2667319 2667863 639081 7329591 0514442 16-08-91 03-04-92 17-04-92 15-07-93 03-09-91 25-11-92 Pemwin PCTflSA/210 (ODOMn. &MM. Pishinds) UuI it 1"l2)